There is a growing interest in developing therapeutic agents with increased selectivity. The ability of a therapeutic agent to affect a particular population of cells in preference over others is a highly desirable property. A therapeutic agent or drug having low selectivity leads to reduced efficacy and higher toxicity. For example, a major limitation of many cancers treatments is their low selectivity for tumor cells. Radiation therapy and alkylating agents perturb many functions that are common to both tumor and normal cells.
HDACs are key enzymes involved in the epigenetic regulation of histone and non-histone proteins (Witt, O. et al. 2009). They modulate protein structure and function through deacetylation of lysine residues. In cancer biology, the involvement of HDACs has been well documented, supporting the notion that altered expression of HDACs could have an active role in tumor development (Haberland, M. et al. 2009; Bolden, J. E. et al. 2006). Consistent with this, the therapeutic potential of HDAC inhibitors (HDACi) is recognized as a new class of drug for cancer (Bolden, J. E. et al. 2006; Minucci, S. et al. 2006; Marks, P. A. & Xu, W. S. 2009). HDAC inhibitors (HDACi), which were developed as single target agents, are a new class of drugs for cancer (Minucci, S. & Pelicci, P. G. 2006; Bolden, J. E. et al. 2006; Marks, P. A. & Xu, W. S. 2009). Currently a number of HDACi are in clinical trials for various hematologic and solid tumors (Marks, P. A. & Xu, W. S. 2009; Wagner, J. M. et al. 20104). In preclinical studies, several HDACi have been found to have potent anticancer effects. However, adverse side effects have been reported in a number of preclinical trials (Bolden, J. E. et al. 2006; Wagner, J. M. et al. 2010). Therefore, selectivity remains a major challenge. Also, since certain HDACs are essential for normal cells, a single target agent using these pharmacologic inhibitors depends on the tolerance levels of normal cells to the damage caused by the treatment (Lee, J. H. et al. 2010; Bhaskara, S. et al. 2010).
Tumor-associated cysteine protease CTSL also plays crucial roles at multiple stages of tumor progression and metastasis (Joyce, J. A. et al. 2004; Jedeszko, C. et al. 2004; Gonzalez-Suarez, I. et al. 2011). Cell lines transformed by certain oncogenes including Ras are known to express high levels of CTSL (Collette, J. et al. 2004; Denhardt, D. T. et al. 1987; Joseph, L. J. et al. 1988). Thus, the upregulation of CTSL is recognized as a hallmark of metastatic cancers and could be utilized as a prognostic marker (Joyce, J. A. et al. 2004; Jedeszko, C. et al. 2004; Gonzalez-Suarez, I. et al. 2011; Tian, Y, et al. 2011; Grotsky, D. A. et al. 2013). Recently, nuclear-localized CTSL involved in cancer has been revealed, suggesting that CTSL may have key roles in the nucleus beyond its known lysosomal and extracellular activities (Gonzalez-Suarez, I. et al. 2011; Grotsky, D. A. et al. 2013; Goulet, B. et al. 2004; Goulet, B. et al. 2007). Although the therapeutic potential of CTSL inhibitors has not been fully characterized in preclinical studies, targeting CTSL activity is considered as a strategy for anticancer therapy (Lankelma, J. M. et al. 2010).
Therefore, drugs with improved selectivity are still urgently needed to combat cancer and various other diseases. Such selectivity allows for a drug with maximal efficacy and minimal adverse effects or toxicity.